Adiponectin: an indispensable molecule in rosiglitazone cardioprotection following myocardial infarction.
Adiponectin: an indispensable molecule in rosiglitazone cardioprotection following myocardial infarction.
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DOI：
10.1161/circresaha.109.211797
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发表时间：
2010-02-05
影响因子：
20.1
通讯作者：
Ma XL
中科院分区：
文献类型：
--
作者：
Tao L;Wang Y;Gao E;Zhang H;Yuan Y;Lau WB;Chan L;Koch WJ;Ma XL
使用过氧化物酶体增殖物激活受体-γ (PPAR-γ) 激动剂治疗的患者表现出与血浆脂联素 (APN) 增加相关的良好代谢特征。然而，PPAR-γ 激动剂治疗导致 APN 产生增加是否是一种附带现象，或者与 PPAR-γ 的心脏保护作用有因果关系，仍然完全未知。确定 APN 在罗格列酮 (RSG) 预防缺血性心脏损伤的心脏保护中的作用。用载体或罗格列酮（RSG，20 mg/kg/天）治疗成年雄性野生型（WT）和APN敲低/敲除（APN+/-和APN−/−）小鼠，并在开始治疗后3天进行冠状动脉结扎。在WT小鼠中，RSG（7天）显着增加脂肪细胞APN表达，升高血浆APN水平（2.6倍），减少梗塞面积（减少17%），减少细胞凋亡（0.23±0.02% vs. 远端非缺血区域TUNEL阳性0.47±0.04%），减弱氧化应激（减少48.5%），并改善心功能（P<0.01）。 RSG 诱导的 APN 产生和心脏保护作用在 APN+/- 小鼠中显着减弱（与 WT 相比，P<0.05），在 APN−/− 小鼠中完全丧失（与媒介物处理的 APN−/− 小鼠相比，P>0.05）。此外，RSG 治疗长达 14 天显着提高了 WT 小鼠的缺血后存活率（与载体组相比，P<0.05），但 APN 敲除/基因敲除小鼠则没有。 PPAR-γ 激动剂的心脏保护作用严重依赖于其 APN 刺激作用，这表明在 APN 表达受损的病理条件下（例如晚期 2 型糖尿病），PPAR-γ 激动剂的有害心血管作用可能超过其心脏保护作用。
Patients treated with peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist manifest favorable metabolic profiles associated with increased plasma adiponectin (APN). However, whether increased APN production as a result of PPAR-γ agonist treatment is an epiphenomenon or is causatively related to PPAR-γ’s cardioprotective actions remains completely unknown. To determine the role of APN in rosiglitazone (RSG) cardioprotection against ischemic heart injury. Adult male wild type (WT) and APN knockdown/knockout (APN+/− and APN−/−) mice were treated with vehicle or rosiglitazone (RSG, 20 mg/kg/day), and subjected to coronary artery ligation 3 days after beginning treatment. In WT mice, RSG (7 days) significantly increased adipocyte APN expression, elevated plasma APN levels (2.6-fold), reduced infarct size (17% reduction), decreased apoptosis (0.23±0.02% vs. 0.47±0.04% TUNEL positive in remote non-ischemia area), attenuated oxidative stress (48.5% reduction), and improved cardiac function (P<0.01). RSG-induced APN production and cardioprotection were significantly blunted (P<0.05 vs. WT) in APN+/−, and completely lost in APN−/− (P>0.05 vs. vehicle-treated APN−/− mice). Moreover, treatment with RSG for up to 14 days significantly improved the post-ischemic survival rate of WT mice (P<0.05 vs. vehicle group), but not APN knockdown/knockout mice. PPAR-γ agonists’ cardioprotective effects are critically dependent on its APN stimulatory action, suggesting that under pathologic conditions where APN expression is impaired (such as advanced type-2 diabetes), the harmful cardiovascular effects of PPAR-γ agonists may outweigh its cardioprotective benefits.